The long-term goal of this project is to understand host responses to Ebolavirus infections. To address this question, we propose a 'Systems Biology1 approach that will use mouse and macaque infection models, cell culture and biochemical assays, and high-throughput genomic and proteomic analyses to identify cellular response networks to Ebolavirus infection, and the underlying features of protective immunity afforded by successful vaccination. In Aim 1, we will assess the contribution of RIG-I and TLR3/7-signaling to innate immune responses to Ebolavirus infection. RIG-I and TLR3/7 signaling pathways are now recognized as major players in innate immune responses; their significance for innate immune responses to Ebolavirus infections, however, is currently unknown and will therefore be addressed in this aim. To identify additional host response networks that critically affect the outcome of Ebolavirus infections, we will test wild-type and mutant Ebolaviruses in wild-type, knock-out, and genetically diverse mice in Aim 2; the latter studies will allow the identification of host susceptibility alleles. Ebolavirus mutants will include variants possessing mutations in the VP24 and VP35 proteins which are known to affect the interferon antagonist activity of these proteins. Moreover, we will carry out infection, genomics, proteomics, and metabolomics studies in nonhuman primates, the gold standard for filovirus infection studies. In Aim 3, we plan to determine the mechanisms of protective immune responses induced by Ebolavirus vaccines. The availability of a candidate vaccine that protects mice and nonhuman primates from challenge with lethal doses of Ebolavirus will allow us to dissect the underlying mechanisms for protection. Collectively, the proposed studies will provide novel insights into the network of host responses that determine the outcome of Ebolavirus infections, and may thus suggest novel approaches to the treatment of Ebolavirus infections.